Micronucleus induction in V79 cells by the anabolic doping steroids desoxymethyltestosterone (madol) and 19-norandrostenedione.
The abuse of anabolic steroids for doping raises concerns. Many of these compounds have never been examined for their toxicological properties. Aside from hormonal (androgenic) activity, anabolic steroids may also exert genotoxic effects. In the present study, we determined the potencies of the "designer steroid" madol (MAD) and the anabolic prohormone 19-norandrostenedione (NA) to induce micronuclei in V79 cells in vitro. CREST analysis was used to differentiate between aneugenic and clastogenic mechanisms of micronucleus induction. Cytotoxicity of the steroids and their influence on the cell cycle were assessed in parallel. In addition, the ability of MAD and NA to increase production of reactive oxygen species and to induce apoptosis were studied. Both agents caused a concentration-dependent increase in the rates of micronuclei in V79 cells, exceeding a doubling of the background micronucleus rates of untreated controls, which was evident at 27microM and 29microM for MAD and NA, respectively. The steroid-induced micronuclei were predominantly kinetochor (CREST)-negative, pointing to a clastogenic mode of action. As cytotoxicity of both compounds is weak (IC(20) value of 300microM for NA and IC(10) of 100microM for MAD), cytotoxicity was unlikely to contribute to their genotoxicity. The observed genotoxicity of both compounds was due neither to apoptosis induction nor to production of reactive oxygen species. However, the ability of both steroids to induce micronuclei appears related to their lipophilicity. Therefore, a "non-specific" chromosomal genotoxicity of MAD and NA, based on hydrophobic interactions, appears likely. This could well result in biologically relevant increases in chromosomal damage as soon as critical concentrations of the agents are reached in vivo. Regarding the current misuse of the steroids for doping, the uncontrolled administration of very high doses must be considered. Therefore it cannot be ruled out that MAD and NA present genotoxic hazards under current misuse conditions by athletes in sports or in body building.
Dorn
Susanne B
SB
IfADo - Leibniz Research Centre for Working Environment and Human Factors, Ardeystr. 67, D-44139 Dortmund, Germany.
Bolt
Hermann M
HM
Thevis
Mario
M
Diel
Patrick
P
Degen
Gisela H
GH
D045930:Anabolic Agents / Q000737:chemistry / Q000633:toxicity*; D000735:Androstenedione / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D000737:Androstenols / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000737:chemistry / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004300:Doping in Sports; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016195:G2 Phase / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000633:toxicity; D008741:Methyl Methanesulfonate / Q000737:chemistry / Q000633:toxicity; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D015162:Micronucleus Tests / Q000379:methods; D008856:Microscopy, Fluorescence / Q000379:methods; D015394:Molecular Structure; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D016196:S Phase / Q000187:drug effects
D045930:Anabolic Agents; D000737:Androstenols; D009153:Mutagens; D017382:Reactive Oxygen Species; D000735:Androstenedione; D008741:Methyl Methanesulfonate; C500374:17-methylandrost-2-en-17-ol; D006861:Hydrogen Peroxide; C002828:19-norandrostenedione; D002166:Camptothecin